Activation of integrins by chemokines is responsible for the entry of naive T cells into lymph nodes Flashcards
Pp327-330 Janeway 7th edition
Entry of naive T cells into lymph nodes and other peripheral lymphoid organs requires the actions of two other protein families. Name these protein families.
The integrins and the immunoglobulin superfamily
What are integrins?
A large family of cell-surface proteins
What are integrins involved in?
Adhesion between cells, and between cells and the extracellular matrix.
Integrins bind tightly to their ……. after receiving signals that induce a change in their ……….
ligands, conformation
Signalling by …….. activates integrins on …….. to bind tightly to the vascular surface in preparation for their migration into sites of inflammation.
chemokines, leukocytes
Chemokines that are present at the luminal surface of _ _ _ activate …………. expressed on the naive T cell during their migration into lymphoid organs
HEV, integrins
List 2 important characteristics of integrins
- An integrin consists of a large alpha chain that pairs noncovalently with a smaller beta chain
- There are several subfamilies of integrins, brouadly defined by their common beta chains.
What chain is common to leukocyte integrins? What is distinct?
A common beta2 chain, and a distinct alpha chain.
All T cells express what integrin? Give three names for this molecule.
- The Beta 2 integrin alphaL:beta2
- CD11a:CD18
- Leukocyte funcitonal antigen 1 (LFA-1)
LFA-1 is found on T cells. What other leukocytes express LFA-1, and what is it involved in?
Macrophages and neutrophils. LFA-1 is involved in their regruitment to sites of infection.
What are the roles of integrin LFA-1 in naive and effector T cells?
- LFA-1 facilitates the migration of naive and effector T cells out of the bloodstream
- LFA-1 is important in the adhesion of naive and effector T cells to their target cells
T cell responses are (normal/abnormal) in patients genetically lacking the B2 integrin chain and hence all B2 integrins. Why?
Normal. Probably because T cells also express other CAMs that may compensate for the absence of LFA-1
List the CAMs expressed by T cells
B2 Integrins
Immunoglobulin superfamily member CD2 B1 integrins
Expression of B1 integrins increases significantly at a late stage in T cell activation. Hence they are also often called .._. What are they important for?
VLAs - very late activation antigens. Important for directing effector T cells to inflamed target tissues.
The antigen receptors of T and B cells are members of the IG superfamily. Name two T cell co-receptors and one B cell co receptor also included in the IG superfamily. What other important cell recognition and adhesion molecule is in this family?
CD4, CD8
CD19
Invarinant domains of MHC molecules.
List five adhesion molecules of the IG superfamily that are especially important in T cell activation. What do they bind?
Intercellular adhesion molecules:
ICAM 1, ICAM 2, ICAM 3 - these all bind T cell integrin LFA-1.
CD2, VCAM-1, and LFA-3
Give another name, the tissue distribution of, and the ligand for CD2
LFA-2, T cells, CD58 (LFA-3)
Give another name, the tissue distribution of, and the ligand for ICAM-1
CD54, Activated vessels, lymphocytes, dendritic cells. LFA-1, Mac-1
Give another name, the tissue distribution of, and the ligand for ICAM-2
CD102, Resting vessels, LFA-1
Give another name, the tissue distribution of, and the ligand for ICAM-3
CD50, Naive T cells, DC-SIGN and LFA-1
Give another name, the tissue distribution of, and the ligand for LFA-3
CD58, lymphocytes, APCs, CD2
Give another name, the tissue distribution of, and the ligand for VCAM-1
CD106, Activated endothelium, VAL-4
CD2, ICAM 1, ICAM 2, ICAM 3, LFA-3, VCAM-1 are all members of what?
The IG superfamily
ICAM 3 is only expressed in one place. What is its role thought to be?
Naive T cells, thought to have an important role in the adhesion of T cells to APC cells, especially DCs.
Where is DC-SIGN found? What T cell integrin binds DC SIGN?
DC-SIGN is found only on DCs. ICAM 3 binds DC-SIGN
The interaction of what APC IG superfamily CAM interacts with CD2 on the T cell? What does this interaction synergise with?
CD58 (LFA-3) binds with CD2. This synergises with that of ICAM-1 or ICAM-2 with LFA-1.
Naive T cells are attracted into the lymph note by ……. secreted by cells in the lymph node
chemokines
Chemokines secreted by cells in the lymph node bind to …………… in the .._ and the .._. This forms a chemical gradient
Chemokines secreted by cells in the lymph node bind to proteoglycans in the ECM and the HEV. This forms a chemical gradient.
The extravasation of naive T cells is prompted by which chemokine?
CCL21
How else is CCL21 known?
Secondary lymphoid tissue chemokine, SLC
What expresses CCL21?
Vascular high endothelial cells
Stromal cells of lymphoid tissues
What naive T cell receptor binds CCL21?
CCR7
Binding of what chemokine and naive T cell receptor causes activation of the intracellular receptor associated G protein subunit G alpha-i? What is the result of this?
When CCL21 binds CCR7 on naive T cells, what does this stimulate?
The results in intracellular signalling that rapidly increases the affinity of integrin binding by an unknown mechanism.
What selectin mediates the inital rolling of a naive T cell along an HEV?
L-selectin
Contact of naive T cells with chemokine CCL21 in the HEV causes what to become activated?
Integrin LFA-1 on the naive T cell
What does activation of Integrin LFA-1 on a naive T cell cause increased affinity for?
ICAM-1 and ICAM-2
Which ICAM is expressed constitutively on all endothelial cells?
ICAM-2
Which ICAM , in the absence of inflammation, is expressed only on the high endothelial cells of peripheral lymphoid tissues?
ICAM-1
The mobility of ………… in the T cell membrane is increased by chemokine stimulation. What does this enable?
Integrin. This enables integrin molecules to migrate into the area of cell-cell contact. (This enables stronger binding, arresting the T cell on the endothelial surface so it can enter lymphoid tissue).
What makes CCL21?
Stromal cells in the T cell zones of the PLO
Once naive T cells have arrived in the T cell zone of the PLOs, what directs their migration towar sources of CCL21?
CCR7
CCR7 directs naive T cells in the T cell zone towards sources of CCL21. What other chemokine are the naive T cells directed to?
CCL19, a second chemokine ligand for CCR7
What makes CCL19?
T cell zone stromal cells and to a lesser degree dendritic cells
What chemokine do mature dendritic cells produce? (two names)
CCL18 (DC-CK)
What is the source and role of CCL18?
DCs, attracts naive T cells
What do naive T cells do once they have reached the T cell zone of PLOs?
They scan the surfaces of dendritic cells for specific peptide:Mhc complexes
Via what route to unstimulated naive T cells exit a lymph node?
Via the cortical sinuses, which lead to the medullary sinus, then to the efferent lymphatic vessel
What lipid molecule is involved in T cell egress from PLOs? How?
sphingosine 1-phosphate (S1P), T cells expressing S1P receptors migrate along a concentration gradient
What properties does sphingosine 1-phosphate have?
Chemotactic activity and signalling properties similar to chemokines
What type of receptors are those for S1P? What else has this type of receptor?
G-protein coupled receptors, chemokines.
What receptor to naive T cells down regulate when they are activated?
S1P g-protein coupled receptors
What downregulated receptor to effector T cells re-respress after several days of proliferation?
Sphingosine 1-phosphate (S1P)
What drug is involved in the regulation of exit from PLOs by naive and effector T cells?
FTY720
What does the immunosuppressant FTY720 cause?
FTY 720 inhibits immune responses in animal models of transplantation by preventing lymphocytes from returning to circulation, causing lymphopaenia
What is the mechanism of action by which FTY720 causes lymphopaenia?
FTY720 becomes phosphorylated, and mimics S1P as an agonist at S1P receptors. Phosphorylated FTY720 may inhibit lymphocyte exit by effects on endothelial cells that increase tight junction formation and close exit portals, or by chronic activation of S1P receptors, leading to inactivation and downregulation of the receptor
